This invention relates to a method for preparation of polymer compositions for encapsulation of biological materials, especially living cells.
A number of different polymers have been used for controlled drug delivery. Synthetic polymers are preferred over natural polymers for their reproducibility and ease of manufacture. Examples of biodegradable polymers include poly(anhydrides), poly(orthoesters), and poly(lactic acid). Examples of "non-degradable" polymers include ethylene vinyl acetate and poly(acrylic acid). The use of polyphosphazenes for controlled drug delivery was described in U.S. Ser. No. 07/060,770 filed Jun. 10, 1987 by Laurencin, et al., and in U.S. Pat. No. 4,880,622 to Allcock, et al. The polymers described by U.S. Pat. No. 4,880,622 to Allcock, et al., and in U.S. Ser. No. 07/060,770 by Laurencin, et al., are formed into drug delivery devices by standard techniques, including dissolution and casting of the polymer into a film or disk, dissolution of the polymer and crosslinking by covalent bonding or by irradiation to form a soft gel, or compression of polymer particles into a disk.
Synthetic polymers are used increasingly in medical science due to the chemist's ability to incorporate specific properties such as strength, hydrogel characteristics, permeability or biocompatability, particularly in fields like cell encapsulation and drug delivery where such properties are often prerequisites. However, harsh conditions, e.g., heat or organic solvents, are always used when encapsulating with these polymers, often causing difficulties in encapsulating sensitive entities, e.g., proteins, liposomes, mammalian cells.
Up until now most entrapment methods used for the microencapsulation of mammalian cells have been based on natural polymers such as agarose or alginates. Agarose gel microbeads can be formed by emulsification of an agarose-parafilm oil mixtures or by using teflon molds. In either case, the temperature-mediated gelation of agarose required the use of temperature extremes which are harmful to cells. Alginate, on the other hand, can be ionically cross-linked with divalent cations, in water, and room temperature to form a hydrogel matrix. Due to these mild conditions, alginate has been the most commonly used polymer for hybridoma cell encapsulation. This polymer can be ionically cross-linked in water to form hydrogels as described in U.S. Pat. No. 4,352,883 to Lim. In this process, an aqueous solution containing the biological materials to be encapsulated is suspended in a solution of a water soluble polymer, the suspension is formed into droplets which are configured into discrete microcapsules by contact with multivalent cations, then the surface of the microcapsules are crosslinked to form a semipermeable membrane around the encapsulated materials.
However, natural polymers display variable biocompatability and some properties can be reproduced only with difficulty, due to impurities in the preparation extracts. Synthetic polymers are better to use because of reproducibility and the chemist's ability to tailor their properties according to specific needs. For purposes of greater control over composition and ease of manufacture, it would be preferable to have a method to encapsulate biological materials using synthetic polymers rather than polysaccharides, as described by Lim. It would also be advantageous to be able to make either biodegradable or non-degradable compositions. To date, no one has been able to encapsulate biological materials in synthetic polymers without using elevated temperatures or organic solvents.
It is therefore an object of the present invention to provide a method and compositions for encapsulating biological materials in synthetic polymers without the use of elevated temperatures or organic solvents.
It is a further object of the present invention to provide a method and compositions for encapsulating biological materials in either hydrolytically degradable or non-hydrolytically degradable synthetic polymers